BACKGROUND: Artemisinin combination therapies (ACTs) with broad
efficacy are needed where multiple Plasmodium species are
transmitted, especially in children, who bear the brunt of
infection in endemic areas. In Papua New Guinea (PNG),
artemether-lumefantrine is the first-line treatment for
uncomplicated malaria, but it has limited efficacy against P.
vivax. Artemisinin-naphthoquine should have greater activity in
vivax malaria because the elimination of naphthoquine is slower
than that of lumefantrine. In this study, the efficacy,
tolerability, and safety of these ACTs were assessed in PNG
children aged 0.5-5 y. METHODS AND FINDINGS: An open-label,
randomized, parallel-group trial of artemether-lumefantrine (six
doses over 3 d) and artemisinin-naphthoquine (three daily doses)
was conducted between 28 March 2011 and 22 April 2013.
Parasitologic outcomes were assessed without knowledge of
treatment allocation. Primary endpoints were the 42-d P.
falciparum PCR-corrected adequate clinical and parasitologic
response (ACPR) and the P. vivax PCR-uncorrected 42-d ACPR.
Non-inferiority and superiority designs were used for falciparum
and vivax malaria, respectively. Because the
artemisinin-naphthoquine regimen involved three doses rather
than the manufacturer-specified single dose, the first 188
children underwent detailed safety monitoring. Of 2,542 febrile
children screened, 267 were randomized, and 186 with falciparum
and 47 with vivax malaria completed the 42-d follow-up. Both
ACTs were safe and well tolerated. P. falciparum ACPRs were
97.8% and 100.0% in artemether-lumefantrine and
artemisinin-naphthoquine-treated patients, respectively
(difference 2.2% [95% CI -3.0% to 8.4%] versus -5.0%
non-inferiority margin, p = 0.24), and P. vivax ACPRs were 30.0%
and 100.0%, respectively (difference 70.0% [95% CI 40.9%-87.2%],
p<0.001). Limitations included the exclusion of 11% of
randomized patients with sub-threshold parasitemias on
confirmatory microscopy and direct observation of only morning
artemether-lumefantrine dosing. CONCLUSIONS:
Artemisinin-naphthoquine is non-inferior to
artemether-lumefantrine in PNG children with falciparum malaria
but has greater efficacy against vivax malaria, findings with
implications in similar geo-epidemiologic settings within and
beyond Oceania. TRIAL REGISTRATION: Australian New Zealand
Clinical Trials Registry ACTRN12610000913077 Please see later in
the article for the Editors' Summary.